Visual function is the most important in the sensory functions and 80% of information from the outer world is inputted through visual system. Therefore, visual dysfunction such as low vision or ablepsia is one of the most serious physical handicaps. In view of the fact that aging of people is proceeding in an information-oriented society, to prevent visual dysfunction would be one of the most important tasks of today's medicine. The importance of improving the QOL (quality of life) of patients in the treatment of the patients who have difficulties in daily life has been advocated. In ophthalmic diseases, it is essential to improve QOLV (quality of life and vision) including improvement and maintaining of visual function, so that it is an urgent task to establish a therapeutic method for attaining this.
Although severe low vision and ablepsia may be caused by various causes, those which are most likely to be the direct cause are retinochoroidal diseases including so called retinal neovascular diseases such as diabetic retinopathy and neovascular maculopathy; detachment of retina; choroiditis; and pigmentary retinal degeneration and macular dystrophy which are hereditary diseases. Therapies of these diseases include chemotherapies, photocoagulation operations and operations of hyaloid body. However, their effectiveness is not satisfactory and it is strongly demanded to develop a chemotherapy which is surely effective. When compared with the photocoagulation operations and operations of hyaloid body, which would accompany with invasion and serious stress, chemotherapy has great advantages that the invasion is smaller and to perform therapy is easier. Thus, development of chemotherapies against increasing various ophthalmic diseases is strongly desired. However, so far, the number of highly effective drugs is small.
On the other hand, with the recent progress of the basic and clinical studies, pathological clarification of retinochoroidal diseases is progressing. That is, it has been getting clearer that paropsis is caused not only by pathological change of visual cells in retina which is a sense organ in the narrow sense, but also by pathological change of retinal pigment epithelium which plays a great role in the metabolism of visual cells, disorders of nerve fibers, circulatory disorder of retina, and by circulatory disorder of choroid.
Especially, the important role of retinal pigment epithelial (RPE) cells in sustaining visual cells has been more and more clarified. That is, the cells are aligned in one layer, that is, in the lowest layer in the retina, on the Bruch's membrane, and absorb the light reached to the retina so as to prevent reflection. Further, the RPE cells constitute the blood-retinal barrier which partitions the visual cells and the vascular layer of choroid together with the Bruch's membrane, and participate in production of various cytokines. Thus, RPE cells have important physical and physiological functions, such as sustainment and regeneration of visual cells.
Recent studies revealed that the cytokines to which RPE cells relate include an accelerator and an inhibitor for neovascularization, so that RPE cells control generation, development, inhibition and degeneration of choroidal neovascularity (as a review article, Yasuhiko TANAKA, Ophthalmology, 31, 1233-1238, 1989; or Masanobu UYAMA, Journal of Japan Ophthalmology Association, 95, 1145-1180, 1991).
It is expected that cultivating RPE cells and making physiological and pathological studies on the RPE cells will greatly contribute to the clarification of physiological functions and pathological state of the eye, and to development of therapeutic methods. However, studies on the factors modifying functions of the RPE cells are in the beginning. It has been clarified only that interleukin (IL)-1.beta., IL-6, IL-8, TNF (tumor necrosis factor), GM-CSF (granulocyte-macrophage colony stimulating factor), MCP (monocyte chemotactic protein) and bFGF (basic fibroblast growth factor) stimulate the growth of RPE cells and TGF .beta. (transforming growth factors-.beta.) inhibits growth of RPE cells (Makoto TAMAI, Journal of Japan Ophthalmology Association, 97, 1-2, 1993). Further, these biological modifying factors have various actions, so that a selective pharmacological action on the RPE cells by these factors is not expected.
As described above, in spite of the fact that the retinochoroidal diseases which may cause serious visual dysfunction and ablepsia are expected to increase, sufficient therapeutic methods therefor have not been established, and histological and functional studies of the RPE cells which are thought to greatly influence on these diseases are now only in the beginning. Further, studies on therapy and prevention of retinochoroidal diseases by proliferation and activation of RPE cells have initiated.
As mentioned above, a task is to develop a factor which proliferates and activates RPE cells, as a therapeutic agent against retinochoroidal diseases against which no effective therapeutic drugs exist. Among the retinochoroidal diseases related to alteration of RPE cells, which accompany with serious visual dysfunction, pigmentary retinal degeneration, for example, is a hereditary disease. Only nosotropic treatments such as administration of a vasodilator or vitamin A are applied to this disease and there is no fundamental therapeutic method therefor. It is thought that a factor which proliferates and activates RPE cells may be a useful drug against such a disease.
On the other hand, as for retinopathy, maculopathy or dystrophy, which accompanies neovascularization, although photocoagulation by using laser beam may be effective in some cases, there are no fundamental chemotherapeutic methods so far. Although photocoagulation by laser beam has a hemostatic effect, heat coagulation spans to the inner layer of retina, so that the function of the retina is lost in a large area. Therefore, this method cannot be applied to cases where the diseased part is in the macular central pit which controls the central vision. Further, therapy by photocoagulatization cannot be performed in cases where choroidal neovascularity exists in the vicinity of central pit. Still further, it is problematic that recurrence of neovascularization often occurs after photocoagulation. Effective chemotherapy is demanded also in order to compensate these drawbacks of photocoagulation. Since RPE cells are known to produce an inhibitor for neovascularization in the growth phase (according to the review by UYAMA, infra), a growth factor of RPE cells may be used as an inhibitor for neovascularization, which may be applied to an alternative or combined therapy with photocoagulation.
In cases where primary or secondary retinal detachment is to be treated, a drug which promotes adhesion of retina is demanded. In cases where heat coagulation (diathermy), coagulation by freezing or photocoagulation is performed, which closes lacuna in the retina by cicatrization, a drug which promotes cicatrization is also demanded. In these cases, a drug which grows RPE cells that play a major role in cicatrization is thought to be applied as a therapeutic agent for detachment of retina.
Thus, developing a novel agent for growing RPE cells, which may be easily applied to intractable diseases such as retinopathy, maculopathy, retinal dystrophy, dystrophy and retinal detachment, is strongly demanded.